The overall goal of this project is to develop novel neuroprotective or therapeutic treatments for stroke, the third leading cause of death and disability in the US. The approach presented is based on the discovery of a subset of genes found to be induced in the mouse brain in an in-vivo model of ischemic tolerance where in a brief non injurious period of ischemia (middle cerebral artery occlusion - MCAO) results in the brain being "tolerant" to a subsequent MCAO. One of these gene products, osteopontin (OPN), has been tested in this mouse stroke model and found to induce a significant level of neuroprotection when the protein is introduced directly into the brain ventricles immediately prior to and following the stroke. The specific aims of this STTR project are designed to assess the suitability of this methodology to drug development. The aims are to: 1) test whether OPN is neuroprotective only (i.e. protective only when administered prior to ischemia), therapeutic only (i.e. effective only when administered after ischemia) or both. 2) to test whether a peptide mimic of OPN can provide the same level of neuroprotection as the protein itself when administered intrathecally; and 3) to use high density DNA micro array methodology to survey the pattern of gene expression in the brain after the stroke event in the presence and absence of neuroprotective factors to identify other molecular modulators of this neuroprotective system.